This revised R01 application focuses on elucidating the cell type specific functions of the Fmr1 gene in the pathogenesis of social impairments that characterize autism spectrum disorder (ASD); a first step in a larger project aimed at identifying circuit based approaches which could act as therapeutics for treating ASD. Based on extensive preliminary findings, our overall hypothesis is that the loss of Fmr1 gene function in oxytocin (OT) neurons leads to disruption of mechanisms that normally subserve social reward learning, and that closure of the social reward learning critical period limits the efficacy of therapeutic interventions delivered in adulthood. Our hypothesis was formulated based on research in our laboratory demonstrating that acute deletion of Fmr1 in parvocellular OT neurons projecting to the nucleus accumbens (NAc) recapitulates social reward learning phenotypes observed in constitutive Fmr1 KO mice. In addition, we have discovered a novel critical period for social reward learning, and identified manipulations to reinstate social reward learning in adulthood. Despite our important preliminary findings, the importance of subtypes of OT neurons in ASD relevant phenotypes is unknown and only minimally been explored. Building on our preliminary insights, we propose to address a number of outstanding questions concerning the cellular, synaptic, circuit, and developmental consequences of Fmr1 deletion, outlined below in Aims 1-4: Aim 1: To determine the molecular and cellular consequences of Fmr1 deletion in oxytocin (OT) neuronal subtypes. Here we will test the hypothesis that cellular characteristics of parvocellular OT neurons will be selectively impacted by deletion of the Fmr1 gene. Aim 2: To determine the consequences of Fmr1 deletion on OT dependent synaptic plasticity. Here we will test the hypothesis that deletion of Fmr1 will lead to an impairment of OT synaptic plasticity in the nucleus accumbens (NAc). Aim 3: To determine the functional selectivity of OT neuronal subtypes. Here we will test the hypothesis that peer-peer social reward learning deficits will be social domain specific following ablation of OT neurons projecting to the NAc, but not the VTA. Aim 4: To determine the impact of the critical period for social reward learning on the therapeutic approach to Fragile X. Here we will test the hypothesis that social reward learning deficits in Fmr1 KO mice can be corrected if therapeutic interventions are delivered either before the closure of this critical period, or in adulthood if given in conjunction with manipulations that reopen the social reward learning critical period. In addition, the studies proposed in Aims 1-4 will deliver several novel tools for functional genomics. These tools will allow us to perform sophisticated molecular, synaptic and circuit level manipulations. It is our hope that the proposed experiments will provide new insight into how cell type specific mechanisms underlying social reward behavior contribute to the pathogenesis of social deficits in ASD.